The present invention relates to anti-viral compounds and their use in the fields of pharmaceutical and medicinal chemistry.
The incidence of viral upper respiratory disease, the common cold, is immense. It has been estimated that nearly a billion cases annually appear in the United States alone. Rhinovirus, a member of the picornaviridae family, is the major cause of the common cold in humans. Since more than 110 strains of rhinovirus have been identified, the development of a comprehensive rhinovirus vaccine is not practical. Accordingly, chemotherapy appears to be a more desirable approach. Another member of the picornavirus family is the enterovirus, which includes approximately eighty human pathogens. Many of these enteroviruses cause cold-like symptoms; others can cause more serious diseases such as polio, conjunctivitis, aseptic meningitis and myocarditis.
Illness related to rhinovirus infection is evidenced by nasal discharge and obstruction. Furthermore, it has been implicated in otitis media, predisposes the development of bronchitis, exacerbates sinusitis, and has been implicated in the precipitation of asthmatic disease. Although it is considered by many to be a mere nuisance, its frequent occurrence in otherwise healthy individuals and the resulting economic importance has made rhinovirus infection the subject of extensive investigation.
The ability of chemical compounds to suppress the growth of viruses in vitro may be readily demonstrated using a virus plaque suppression test or a cytopathic effect test (CPE). Cf Siminoff, Applied Microbiology, 9(1), 66 (1961). Although a number of chemical compounds that inhibit picornaviruses have been identified, many are unacceptable due to 1) limited spectrum of activity, 2) undesirable side effects or 3) inability to prevent infection or illness in animals or humans. See Textbook of Human Virology, edited by Robert B. Belshe, chapter 16, xe2x80x9cRhinoviruses,xe2x80x9d Roland A. Levandowski, 391-405 (1985). Thus, despite the recognized therapeutic potential associated with a rhinovirus inhibitor and the research efforts expended thus far, a viable therapeutic agent has not yet emerged. For example, antiviral benzimidazole compounds have been disclosed in U.S. Pat. Nos. 4,008,243, 4,018,790, 4,118,573, 4,118,742 and 4,174,454.
Accordingly, the present invention provides novel pyridoimidazole compounds which inhibit the growth of picornaviruses, such as rhinoviruses (bovine and human) and the like; enteroviruses, such as polioviruses and the like; coxsackieviruses of the A and B groups, or echo virus; cardioviruses, such as encephalomyocarditis virus (EMC) and the like; apthoviruses, such as foot and mouth disease virus and the like; and Hepatitis viruses, such as Hepatitis C virus, and the like.
The present invention provides compounds of Formula (I): 
wherein:
A is phenyl, pyridyl, substituted phenyl, substituted pyridyl, or benzyl;
R is hydrogen, COR4, or COCF3;
X is Nxe2x80x94OH, O, or CHR1;
R1 is hydrogen, halo, CN, C1-C4 alkyl, xe2x80x94Cxe2x89xa1CH, CO(C1-C4 alkyl), CO2(C1-C4 alkyl), or CONR2R3;
R2 and R3 are independently hydrogen or C1-C4 alkyl;
Axe2x80x2 is hydrogen, halo, C1-C6 alkyl, benzyl, naphthyl, thienyl, furyl, pyridyl, pyrrolyl, COR4, S(O)nR4, or a group of the formula 
R4 is C1-C6 alkyl, phenyl, or substituted phenyl;
n is 0, 1, or 2;
R5 is independently at each occurance hydrogen or halo;
m is 1, 2, 3, or 4; and
R6 is hydrogen, halo, CF3, OH, CO2H, NH2, NO2, CONHOCH3, C1-C4 alkyl, or CO2(C1-C4 alkyl), C1-C4 alkoxy;
or pharmaceutically acceptable salts thereof.
The present invention also provides pharmaceutical formulations comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient thereof.
The present invention also provides a method for inhibiting a picornavirus comprising administering to a host in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for inhibiting a Hepatitis C virus comprising administering to a host in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention also provides for the use of compounds of Formula (I) for inhibiting a picornavirus, a rhinovirus, or a Hepatitis virus.
The present invention relates to compounds of formula (I), as described above, that are useful as antiviral agents.
All temperatures stated herein are in degrees Celsius (xc2x0 C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
The term xe2x80x9cC1-C6 alkylxe2x80x9d, as used herein, represents a straight or branched alkyl chain having from one to six carbon atoms. Typical C1-C6 alkyl groups include, but are not intended to be limited to; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, and the like. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkylxe2x80x9d, and includes within its definition cycloalkyl groups wherein the alkylgroup is formed into a ring.
The term xe2x80x9chaloxe2x80x9d represents chloro, fluoro, bromo, or iodo.
The term xe2x80x9csubstituted phenylxe2x80x9d, when used herein, represents a phenyl ring substituted with 1, 2 or 3 substituents independently selected from the group consisting of; halo, C1-C4 alkyl, C1-C6 alkoxy, or trifluoromethyl.
The term xe2x80x9csubstituted pyridylxe2x80x9d, when used herein, represents a pyridyl ring substituted with 1, 2 or 3 substituents independently selected from the group consisting of; halo, C1-C4 alkyl, C1-C6 alkoxy, or trifluoromethyl.
As mentioned above, the invention includes the pharmaceutically acceptable salts of the compounds defined by Formula (I). Although generally neutral, a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic acids and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts include, but are not intended to be limited to, inorganic acids such as; hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as; p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts include, but are not intended to be limited to; sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include, but are not intended to be limited to, those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
The pharmaceutically acceptable salts of the invention are typically formed by reacting a compound of Formula (I) with an equimolar or excess amount of acid or base. The reactants are generally combined in a neutral solvent such as diethyl ether, benzene, and the like, for acid addition salts, or water, alcohols, and the like for base addition salts. The salts normally precipitate out of solution within about one hour to about ten days, and can be isolated by filtration or other conventional methods.
The compounds of the present invention can occur in either the cis or trans configuration, wherein, cis refers to those compounds where the substituent on the alkene moiety is cis to the ring designated xe2x80x9cAxe2x80x9d and trans refers to those compounds where the substituent on the alkene moiety is trans to the ring designated xe2x80x9cAxe2x80x9d. Both isomers and mixtures thereof are included within the scope of the present invention.
The following lettered paragraphs represent preferred embodiments of the present invention, however, it is to be understood that the present invention is not limited to such embodiments and that other embodiments are contemplated. Preferred compounds of Formula (I) are those wherein:
a) A is phenyl, pyridyl, substituted phenyl, or substituted pyridyl;
b) A is phenyl or substituted phenyl;
c) A is difluorophenyl or fluorophenyl;
d) A is pyridyl, substituted phenyl, or substituted pyridyl;
e) R is hydrogen
f) R is COCF3;
g) X is NOH;
h) X is CHR1;
i) R1 is CONR2R3, CO2(C1-C4 alkyl), or CN;
j) R1 is CONR2R3;
k) R1 is CO2(C1-C4 alkyl);
l) R2 and R3 are independently methyl or hydrogen;
m) Axe2x80x2 is C1-C6 alkyl, naphthyl, thienyl, COR4, S(O)nR4, or a group of the formula 
n) Axe2x80x2 is C1-C6 alkyl, COR4, S(O)nR4, or a group of the formula 
o) Axe2x80x2 is a group of the formula 
p) Axe2x80x2 is C1-C6 alkyl, COR4, or S(O)nR4;
q) Axe2x80x2 is COR4, or S(O)nR4;
r) R5 is fluoro and m is 5;
s) m is 1, 2, 3, or 5.
t) R6 is CF3, OH, CO2H, NH2, NO2, CONHOCH3, C1-C4 alkyl, C1-C4 alkoxy;
u) R6 is CF3, OH, CONHOCH3, C1-C4 alkyl, C1-C4 alkoxy; and
v) R6 is CF3, OH, C1-C4 alkyl, C1-C4 alkoxy.
The compounds of formula (I) can be prepared by synthetic methods known in the art and by methods disclosed herein. The compounds of formula (I) wherein Axe2x80x2 is; hydrogen, C1-C6 alkyl, napthyl, thienyl, furyl, pyridyl, pyrrolyl, or a group of the formula 
can be prepared according to Scheme I shown below. 
L represents a leaving group selected from the group consisting of: halo, O-triflate, O-mesylate, O-tosylate, and the like.
Z represents hydrogen, C1-C6 alkyl, napthyl, thienyl, furyl, pyridyl, pyrrolyl, or a group of the formula 
Compounds of Formula (A) can be prepared by synthetic methods known in the art and by methods disclosed herein. For example, compounds of Formula (A) can be prepared according to Scheme II shown below. 
An appropriately substituted aryl group can be acylated under Friedel-Crafts conditions, in the presence of a Lewis Acid, with an appropriately substituted acid anhydride, carboxylic acid, or acid chloride to form the compounds of Formula (H). (See e.g.; Friedel-Crafts and Related Reactions, Ed. G. A., Olah, J. Wiley and Sons, N.Y., chapters 31,32 (1964)) Suitable Lewis acid catalysts include, but are not limited to, trifluoroacetic anhydride/phosphoric acid, trifluoromethanesulfonic acid, iron(III) chloride, zinc chloride, copper triflate (CuOTf), phosphorous oxychloride, trifluoroacetic acid, aluminum trichloride, and the like. Aluminum trichloride is the preferred Lewis acid. Suitable solvents include, but are not limited to, methylene chloride, acetonitrile, 1,2-dichloroethane, nitromethane, lower alcohols, acetonitrile, dimethylsulfoxide, and the like. The reaction is preferably run xe2x80x9cneatxe2x80x9d using the substituted aryl group as the preferred solvent. The substituted aryl group is generally employed in a substantial molar excess. For example, an approximately 3 to 10 molar excess, relative to the 6-chloronicotinoylchloride, is generally employed. A molar excess of about 3.8 is typically preferred. The reaction is preferably carried out at about 80xc2x0 C.
Alternatively, compounds of formula (H) can be prepared by reacting a compound of formula (G) with an aryl anion by methods well known in the art. The Weinreb amide of formula (G) can be prepared from the corresponding 1-chloro-5-nicotinic acid by methods well known in the art. Likewise, the acyl anions utilized to prepare the compounds of formula (H) are well known in the art and can be prepared by methods described in the art. For example, an appropriately substituted bromo or iodo aryl group can be subjected to metal-halogen exchange conditions to afford the metal aryl anion by methods well known in the art and disclosed herein. See Organic Reactions, vol. 6, pg. 339, (1951) for a general discussion of metal-halogen exchange conditions. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, diethyl ether, acetonitrile, tetrahydrofuran, and the like. Tetrahydrofuran is the preferred solvent. Suitable sources of metal include, but are not limited to, molecular lithium, alkyl lithiums, and the like including especially t-butyl lithium. N-Butyl lithium is a preferred source of metal. The metal is generally employed in a slight molar excess. For example, approximately a 1 to 1.1 molar excess is generally employed. A 1.03 molar excess is typically preferred. The reaction is preferably carried out at about xe2x88x9278xc2x0 C. for approximately 15 minutes.
Compounds of formula (H) can be aminated with ammonia under high pressures to yield compounds of formula (J). A compound of Formula (H) is dissolved in a suitable solvent, liquid ammonia added, and the reaction sealed in a vessel resistant to elevated pressures. Suitable solvents include, but are not limited to, toluene, lower alcohols, acetontrile, ethyl ether, tetrahydrofuran, dimethylformamide, chloroform, methylenechloride, and the like. Ethanol is the preferred solvent. The reaction is preferably carried out at about 145xc2x0 C. for approximately 16 hours.
The compounds of formula (A) can be prepared by procedures well known in the art. For example, a compound of formula (J) can be tosylated in an inert solvent by addition of a base and tosyl chloride. Suitable solvents include, but are not limited to, tetrahydrofuran, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform, and the like. Suitable bases include triethylamine, sodium bicarbonate, sodium hydroxide, imidazole, and the like. Pyridine is the preferred base and solvent. The tosyl chloride is generally employed in a slight molar excess. For example, approximately a 1 to 2 molar excess, relative to the compound of formula (J), is generally employed. A 1.1 molar excess is typically preferred. The reaction is preferably carried out at about 90xc2x0 C. for approximately 16 hours.
Compounds of formula (B) can be prepared by synthetic methods known in the art and by methods disclosed herein. For example, compounds of formula (B), wherein L is bromide, can be prepared according to Scheme III shown below. 
An appropriately substituted acetic acid of formula (K) is brominated in an appropriate solvent in the presence of a radical initiator to afford compounds of formula (L). Suitable brominating agents include, but are not limited to, molecular bromine, N-Bromosuccinimide, and the like. N-Bromosuccinimide is the preferred brominating agent. Suitable solvents include, but are not limited to, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, acetonitrile, benzene, dimethylsulfoxide, carbon tetrachloride, and the like. Carbon tetrachloride is the preferred solvent. Suitable radical initiators include, but are not limited to, phosphorous trichloride, molecular phosphorous, benzoylperoxide, UV radiation, and the like. Preferred initators are benzoylperoxide and UV radiation. The brominating reagent is generally employed in a stoichiometric amount. For example, 1 equivalent, relative to the compound of formula (K), is generally employed and is typically preferred. The initiator is generally employed in a catalytic amount. For example, an approximately 0.1 to 1 mole percent, relative to the compound of formula (K), is generally employed. A 0.4 mole percentage is typically preferred. The reaction is preferably carried out at about 77xc2x0 C. for approximately 5 hours.
Compounds of formula (M) can be prepared by amidation of compounds of formula (L) by procedures known in the art. For example, the transformation can be carried out by dissolving or suspending the compound of formula (L) in an appropriate solvent and then adding a nucleophilic source of chlorine to afford the corresponding acid chlorides, which can then be amidated in situ with gaseous ammonia. Suitable solvents include, but are not limited to, alkanes, dimethylformamide, lower alcohols, ethyl acetate, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, chloroform, and the like. Dimethylformamide, methylene chloride, hexanes and toluene are the preferred solvents. Suitable chlorinating agents include, but are not limited to, thionyl chloride, phosphorous pentachloride, bis(trichloromethyl)carbonate, allyl chloroformate, phosphorous trichloride, triphosgene, oxalyl chloride, and the like. Oxalyl chloride is the preferred chlorinating agent. The chlorinating agent is generally employed in a slight molar excess. For example, approximately a 1 to 2 molar excess, relative to the compound of formula (L), is generally employed. A 1.6 molar excess is typically preferred. The ammonia is generally employed in a substantial molar excess. For example, ammonia gas is preferably bubbled through the reaction mixture for approximately one hour delivering an unspecified amount of ammonia. The reaction is preferably carried out at about 0xc2x0 C. when adding the chlorinating agent and then for approximately 3 hours at about 22xc2x0 C. before adding the gaseous ammonia over approximately 1 hour at about 22xc2x0 C.
Additionally, compounds of Formula (B), wherein L is O-tosylate, can be prepared according to Scheme IV shown below. 
The compounds of formula (O) can be prepared from appropriately substituted aldehydes by methods known in the art. For example, a compound of formula (N) is mixed with the acyl anion equivalent of a carboxylate, such as trimethylsilylcyanide, to afford, upon hydrolysis, the compounds of formula (O). Suitable solvents include, but are not limited to, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform, and the like. The reaction is preferably run xe2x80x9cneatxe2x80x9d when either the aldehyde or acyl anion equivalent is a liquid. The acyl anion equivalent is generally employed in a stoichiometric ratio. For example, 1 equivalent of acyl anion, relative to the benzaldehyde, is generally employed and is typically preferred. The reaction is preferably carried out at about 25xc2x0 C. for approximately 72 hours after addition of the acylanion equivalent and then at about 100xc2x0 C. for approximately 18 hours to yield compounds of formula (O).
The compounds of Formula (P) can be prepared from compounds of Formula (O) by methods well known in the art. Acetylation of hydroxyacids is described throughout the art. For example, see Greene T. W., Protective Groups in Organic Synthesis, John Wiley and Sons (1981).
Compounds of formula (Q) can be prepared by amidation of compounds of Formula (P) by procedures well known in the art and disclosed herein. The amidation is substantially analogous to the method utilized to prepare compounds of formula (M) from compounds of formula (L).
The compounds of Formula (Q) can be prepared by removal of the acetyl protecting group in compounds of Formula (P) by methods well known in the art. For example, see Greene T. W., Protective Groups in Organic Synthesis, John Wiley and Sons (1981).
The compounds of Formula (R) which have an alcohol moiety converted to a leaving group are prepared by procedures well known in the art. For example, see Stang, et. al., Synthesis, pp. 85-1266 (1982).
Compounds of Formula (C) can be prepared by methods known in the art and by methods disclosed herein. For example, a compound of Formula (A) is combined with a compound of Formula (B) to afford the compounds of Formula (C). Suitable solvents include, but are not limited to, toluene, tetrahydrofuran, methylene chloride, diethyl ether, acetonitrile, and the like. Dimethylformamide is typically the preferred solvent. Suitable bases include, but are not limited to, cesium fluoride, cesium carbonate, hindered alkyl amines, and the like, including especially diisopropylethyl amine. Sodium hydride is typically the preferred base. The base is generally employed in a slight molar excess. For example, approximately a 1 to 1.25 molar excess, relative to the compound of Formula (A), is generally employed. A 1.1 molar excess is typically preferred. The compound of Formula (B) is generally employed in a slight molar excess. For example, approximately a 1 to 1.1 molar excess, relative to the compound of Formula (A), is generally employed. A 1.05 molar excess is typically preferred. The deprotanation is preferably carried out at room temperature for approximately 1.5 hours. After addition of the compound of Formula (B), the reaction is typically preferably carried out at room temperature for about 7 days.
Compounds of Formula (D) can be prepared by methods known in the art and by methods disclosed herein. For example, a compound of formula (C) can be cyclized by dissolving a compound of formula (C) in a suitable solvent and adding trifluoroacetic anyhdride to afford the compounds of Formula (D). Suitable solvents include, but are not limited to, toluene, dimethylformamide, tetrahydrofuran, diethyl ether, acetonitrile, and the like. Methylenechloride is typically the preferred solvent. The trifluoroacetic anhydride is generally employed in a substantial molar excess. For example, approximately a 5 to 20 molar excess, relative to the compound of Formula (C), is generally employed. A 12.4 molar excess is typically preferred. The reaction is typically preferably carried out at about the reflux temperature of methylene chloride (40xc2x0 C.) for approximately 3 hours.
Compounds of Formula (E) can be prepared by methods known in the art and by methods disclosed herein.
The compounds of Formula (E), wherein X is CHR1 and R1 is CONH2, CO(C1-C4 alkyl), CONR2R3, or CO2(C1-C4 alkyl) can be prepared from compounds of formula (D) by procedures known in the art as well as procedures disclosed herein. For example, an appropriately substituted Horner-Emmons reagent (see Organic Reactions, 1977 Volume 25, pg. 73.) is deprotonated with a strong base in an aprotic solvent and a compound of Formula (D) added to afford compounds of Formula (E). Suitable strong bases include, but are not limited to, alkyl lithiums, lithium diisopropylamine, lithium bistrimethylsilylamide, and the like. Potassium t-butoxide is the preferred base. Suitable solvents include, but are not limited to, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, dimethylsulfoxide, and the like. Dimethylformamide and tetrahydrofuran are the preferred solvents. The Horner-Emmons reagent is generally employed in a slight molar excess. For example, from about a 1 to 2 molar excess, relative to the compound of formula (D), is common. A 1.1 molar excess is typically preferred. The reaction is preferably carried out at about 0xc2x0 C. when adding the compound of Formula (A), and then at about 25xc2x0 C. for approximately 1 hour.
The compounds of Formula (E), wherein X is NOH, can be prepared from compounds of Formula (D) by procedures known in the art as well as procedures disclosed herein. For example, compounds of Formula (D) can be dissolved or suspended in an appropriate solvent and hydroxylamine added to afford the compounds of Formula (E). Suitable solvents include, but are not limited to, lower alcohols, ethyl acetate, methylene chloride, chloroform, and the like. Methanol or pyridine is the preferred solvent. The hydroxylamine is generally employed in a substantial molar excess. For example, from about a 3 to 10 molar excess, relative to the compound of Formula (E), is common. A 5.0 molar excess is typically preferred. The reaction is preferably carried out at about 25xc2x0 C. for approximately 24 hours.
The compounds of Formula (E), wherein X is CHR1, and R1 is H, or CN; can be prepared from compounds of Formula (D) by procedures known in the art as well as procedures disclosed herein. For example, an appropriately substituted Peterson Olefination Reagent (see Organic Reactions, 1990, volume 38, pg. 1.) can be dissolved in a suitable solvent and deprotonated with a strong base. A compound of Formula (D) can then added to the product. Suitable strong bases include, but are not limited to, potassium t-butoxide, alkyl lithiums, lithium diisopropylamine, lithium bistrimethylsilylamide, and the like. N-Butyl lithium is the preferred base. Suitable solvents include, but are not limited to, diethyl ether, methylene chloride, chloroform, dimethylformamide, dimethylsulfoxide, and the like. Tetrahydrofuran is the preferred solvent. The Peterson Reagent is generally employed in a substantial molar excess. For example, from about a 3 to 10 molar excess, relative to the compound of Formula (D), is common. A 5.0 molar excess is typically preferred. The reaction is preferably carried out at about xe2x88x9278xc2x0 C. when deprotonating the Peterson Reagent and when adding the compound of Formula (D), and then at about 25xc2x0 C. for approximately 24 hours.
The compounds of Formula (E), wherein X is CHR1 and R1 is halo, can be prepared from compounds of Formula (E), wherein X is CH2, by procedures known in the art as well as procedures disclosed herein. For example, a compound of Formula (E), wherein X is CH2, can be dissolved in a suitable solvent and an appropriate halogenating agent added to form the product. Suitable solvents include, but are not limited to, methylene chloride, tetrahydrofuran, chloroform, acetonitrile, acetic acid, and the like. Tetrahydrofuran and carbon tetrachloride are the preferred solvents. Suitable halogenating agents include, but are not limited to, benzene seleninyl chloride/aluminum chloride, thionyl chloride, molecular bromine, CsSO4F, NFTh, and the like. The halogenating reagent is generally employed in a slight molar excess. For example, from about a 1 to 2 molar excess, relative to the starting material. A 1.1 molar excess is typically preferred. The reaction is preferably carried out at about xe2x88x9210xc2x0 C. when adding the halogenating agent and then at about 22xc2x0 C. for approximately 1 hour.
A skilled artisan would appreciate that the ratio of cis/trans products isolated by the schemes disclosed herein can vary widely, from completely cis or trans to equally proportions of both, depending upon the starting materials employed and the reaction conditions utilized.
Compounds of formula (I) wherein Axe2x80x2 is COR5 can be prepared according procedures shown in Scheme V outlined below. 
Compounds of Formula (S) can be prepared by methods known in the art and disclosed herein. For example, compounds of Formula (H) can be converted to compounds of Formula (S) in a manner substantially analogous to the conversion of compounds of Formula (D) to those of Formula (E) described herein.
Compounds of Formula (T) can be prepared by methods known in the art and disclosed herein. For example, a compound of Formula (S) and a compound of the formula BrCH2COR5 can be dissolved in an appropriate solvent in the presence of iodide anion to afford the compounds of formula (T). Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, and the like. Acetonitrile is the preferred solvent. Suitable sources of iodide anion include, but are not limited to, iodide salts such as sodium, potassium, and ammonium iodide, and the like. Sodium iodide is the preferred source of iodide anion. The compound of the formula BrCH2COR5 is generally employed in a substantial molar excess. For example, approximately a 2 to 10 molar excess, relative to the compound of Formula (S), is generally employed. A 3.7 molar excess is typically preferred. The iodide anion is generally employed in a substantial molar excess. For example, approximately 2 to 10 molar excess, relative to the compound of Formula (S), is generally employed. A 3.8 molar excess is typically preferred. The reaction is preferably carried out at about the reflux temperature of the solvent for approximately 40 hours.
Compounds of Formula (U) can be prepared by methods known in the art and disclosed herein. For example, a compound of Formula (T), aminonitrile, and a base can be combined and dissolved in an appropriate solvent to afford the compounds of formula (U). Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, and the like. Acetonitrile is the preferred solvent. Suitable bases include, but are not limited to, carbonates, hydroxides, and the like. Potassium carbonate is the preferred base. The aminonitrile is generally employed in a slight molar excess. For example, approximately a 1 to 1.05 molar excess, relative to the compound of Formula (T), is generally employed. A 1.02 molar excess is typically preferred. The base is generally employed in a substantial molar excess. For example, approximately a 2 to 5 molar excess, relative to the compound of Formula (T), is generally employed. A 3.05 molar excess is typically preferred. The reaction is typically preferably carried out at about the reflux temperature of the solvent for approximately 14 hours.
Compounds of formula (I) wherein Axe2x80x2 is S(O)nR5 can be prepared according procedures shown in Scheme VI outlined below. 
Compounds of Formula (W) can be prepared by methods known in the art and disclosed herein. For example, compounds of Formula (V) can be converted to compounds of Formula (W) in a manner substantially analogous to the conversion of compounds of Formula (D) to those of Formula (E) described previously within.
Compounds of Formula (X) can be prepared by methods known in the art and disclosed herein. For example, compounds of Formula (W) can be dissolved in a suitable solvent and an iodinating reagent added to form the compounds of Formula (X). Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, and the like. Acetonitrile is the preferred solvent. Suitable iodinating reagents include, but are not limited to, molecular iodine, N-iodosuccinimide, and the like. N-iodosuccinimide is the preferred iodinating reagent. The iodinating reagent is generally and preferably employed in a stoichiometric or equimolar amount relative to the compound of Formula (W). The reaction is preferably carried out at about 0xc2x0 C. for approximately 15 minutes.
Compounds of Formula (Y) can be prepared by methods known in the art and disclosed within. For example, appropriately substituted sulfides can be reacted with an imidazopyridyl anion or anion equivalent by methods well known in the art. Suitable sulfides include but are not limited to, symetrical sulfides, unsymetrical disulfides, and thiol-sulfonates. The thiol sulfonates can be prepared from the generally commercially available disulfides by methods well known in the art and taught in J. Am. Chem. Soc. 1977, 4405.
Compounds of Formula (Y) can be prepared from compounds of Formula (X) by methods well known in the art and methods disclosed herein. For example, a metal-halogen exchange reaction with a compound of Formula (X), substantially analogous to that described previously in the preparation of compounds of Formula (H), followed by the addition of an appropriately substituted sulfide. The skilled artisan will recognize that in contrast to the preparation of the phenyl anion, which is used to form compounds of Formula (H), where there are no acidic protons, the analogous compounds of Formula (X) have one acidic proton and therefore should be deprotonated with a base before attempting the metal-halogen exchange reaction. Suitable bases include, but are not limited to, molecular lithium, alkyl lithiums, lithium amines such as lithium diisopropyl amine, lithium hydride and the like. Phenyl lithium is the preferred base. T-Butyl lithium is the preferred metal source. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran, and the like. Tetrahydrofuran is the preferred solvent. The base is generally employed in a slight to substantial molar excess. For example, approximately 1.5 to 3 molar excess relative to the compound of Formula (X) is generally employed. A 2.2 molar excess is typically preferred. The metal is generally employed in a slight to substantial molar excess. For example, approximately 1.5 to 3 molar excess relative to the compound of Formula (X) is generally employed. A 2.5 molar excess is typically preferred. The reaction is preferably carried out at about xe2x88x9278xc2x0 C. for approximately 3 minutes after the addition of the base, for approximately 10 minutes after the addition of the metal source, and for approximately 30 minutes after addition of the sulfide.
Alternatively, compounds of Formula (Y), can be prepared from an imidazopyridyl anion equivalent, prepared from compounds of Formula (X) under Ullmann like coupling conditions. See Synthesis, 9-21, (1974) for a review of the Ullmann reaction. For example, a compound of the Formula (X) can be dissolved in a suitable solvent, a copper source is added, followed by an appropriately substituted sulfide. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran, pyridine, and the like. Pyridine is the preferred solvent. Suitable sources of copper include, but are not limited to, molecular copper, copper(I)oxide, and the like. Copper bronze or powdered copper is the preferred source. The copper is generally employed in a slight to substantial molar excess. For example, approximately 1.2 to 3 molar excess relative to the compound of Formula (X) is generally employed. A 1.5 molar excess is typically preferred. The sulfide is generally employed in a slight molar deficiency. For example, approximately a 50 to 95 molar percent, relative to the compound of Formula (X), is generally employed. A 78 molar percent is typically preferred. The reaction is preferably carried out at about 100xc2x0 C. for approximately 80 hours.
As another alternative, compounds of formula (Y) can be prepared from compounds of formula (X) by the use of a palladium catalyzed cross coupling reaction between a compound of the Formula (X) and an appropriately substituted trimethyl-thio-tin, i.e. R4Sxe2x80x94Sn(Alkyl)3. See for example Synth.Commun, 22, (5), p. 683, (1992).
Compounds of Formula (Z) can be prepared by oxidation of compounds of Formula (Y) by procedures well known in the art and disclosed herein. For a general review of the oxidation of sulfides to sulfones, see Comprehenive Organic Synthesis, Volume 7, Ch. 6.2, pg. 762, Pergamon Press, Inc. New York, (1991).
The skilled artisan will recognize that it may become advantageous, although not necessary, to remove the trifluoroacetyl protecting group, found in the above schemes, at various points in the syntheses of the compounds of the present invention. The removal of this protecting group can be accomplished by methods well known in the art and disclosed herein. For example, the trifluoroacetylgroup can be removed by dissolving compounds of Formula (D), (E), (V), (W), (X), (Y), or (Z) in an appropriate solvent then adding a base to afford the corresponding deprotected products. Appropriate bases include, but are not limited to, hydroxides, carbonates, amines, and the like. The preferred base is diisopropylethylamine. Alternatively, the protecting group can be hydrolyzed on a silica gel support. See also Greene T. W., Protective Groups in Organic Synthesis, John Wiley and Sons (1981).
In general, the reactions of Schemes I-VI are substantially complete in about 15 minutes to 72 hours when conducted at a temperature range of from about xe2x88x9278xc2x0 C. to the reflux temperature of the reaction mixture. A skilled artisan would appreciate that the rate of a reaction generally increases with an increase in temperature. It is often advantageous, although not necessary, however, to conduct reactions at a slower rate to better control the number and quantity of side products generated. The choice of reaction solvent is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. Once a reaction is complete, the intermediate compound may be isolated, if desired, by procedures known in the art. For example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation, or decantation. The intermediate may be further purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina. The compounds of Formula A-Z are preferably isolated before use in subsequent reactions.